Which Molecules Enter & Leave The Krebs Cycle?

The Krebs cycle, also known as the citric acid cycle or the tricarboxylic acid (TCA) cycle, takes place in the mitochondria of eukaryotic organisms. It is the first of two formal processes associated with aerobic respiration. The second being the electron transport chain (ETC) reactions.

The Krebs cycle is preceded by glycolysis, which is the breakdown of glucose into pyruvate, with a small amount of ATP (adenosine triphosphate, the "energy currency" of cells) and NADH (the reduced form of nicotinamide adenine dinucleotide) generated in the process. Glycolysis and the two aerobic processes that follow it represent complete cellular respiration.

Although ultimately aimed at generating ATP, the Krebs cycle is an indirect, though vital, contributor to the eventual high ATP yield of aerobic respiration.

The starting molecule for glycolysis is the six-carbon sugar glucose, which is the universal nutrient molecule in nature. After glucose enters a cell, it is phosphorylated (i.e., it has a phosphate group attached to it), rearranged, phosphorylated a second time and split into a pair of three-carbon molecules, each with its own phosphate group attached.

Each member of this pair of identical molecules undergoes another phosphorylation. This molecule is rearranged to form pyruvate in a series of steps that generate one NADH per molecule, the four phosphate groups (two from each molecule) are used to create four ATP. But because the first part of glycolysis requires an input of two ATP, the net result of glucose is two pyruvate, one ATP and two NADH.

A Krebs cycle diagram is indispensable when trying to visualize the process. It begins with the introduction of acetyl coenzyme A (acetyl CoA) into the mitochondrial matrix, or organelle interior. Acetyl CoA is a two-carbon molecule created from the three-carbon pyruvate molecules from glycolysis, with CO₂ (carbon dioxide) shed in the process.

Acetyl CoA combines with a four-carbon molecule to kick off the cycle, creating a six-carbon molecule. In a series of steps involving the loss of carbon atoms as CO₂ and the generation of some ATP along with some valuable electron carriers, the six-carbon intermediate molecule is reduced to a four-carbon molecule. But here's what makes this a cycle: This four-carbon product is the same molecule that combines with acetyl CoA at the start of the process.

The Krebs cycle is a wheel that never stops turning as long as acetyl CoA is fed into it to keep it spinning along.

The only reactants of the Krebs cycle proper are acetyl CoA and the aforementioned four-carbon molecule, oxaloacetate. The availability of acetyl CoA hinges on adequate amounts of oxygen being present to suit the needs of a given cell. If the owner of the cell is exercising vigorously, the cell may have to rely almost exclusively on glycolysis until the oxygen "debt" can be "paid" during reduced exercise intensity.

Oxaloacetate combined with acetyl CoA under the influence of the enzyme citrate synthase to form citrate, or equivalently, citric acid. This releases the coenzyme portion of the acetyl CoA molecule, freeing it for use in the upstream reactions of cellular respiration.

Citrate is sequentially converted to isocitrate, alpha-ketoglutarate, succinyl CoA, fumarate and malate before the step that re-generates oxaloacetate takes place. In the process, two CO₂ molecules per turn of the cycle (and thus four per molecule of glucose upstream) are lost to the environment, while the energy liberated in their release is used to generate a total of **two ATP, six NADH and two FADH₂** (an electron carrier similar to NADH) per glucose molecule entering glycolysis.

Looked at differently, taking oxaloacetate out of the mix altogether, when a molecule of acetyl CoA enters the Krebs cycle, the net result is some ATP and a great deal of electron carriers for the subsequent ETC reactions in the mitochondrial membrane.